DESCRIPTION: (Adapted from the applicant's abstract and Specific Aims.) Airway mucociliary clearance is impaired in bronchial asthma, and the impairment appears to be caused by airway inflammation. Altered mucociliary function can compromise airway defenses against bacteria. Since a direct effect of inflammatory cell products on the airway epithelium does not fully explain this defect, it may be that the endothelial cells of the airway microvasculature which forms an extensive subepithelial network, could have an intermediary role between inflammatory cells and the epithelium.The application hypothesizes that the stimulation of the airway endothelium by soluble products of inflammatory cells leads to the release of endothelin-1 (ET-1) and possibly other peptides which cause alterations in the ciliary activity and glycoconjugate profiles of the airway epithelium and its secretions. This could inhibit the removal of bacteria by ciliary action and facilitate the binding of bacteria to the epithelial glycocalyx. To test this hypothesis, the Specific Aims are to: 1) determine if granulocyte mediators (primarily lipids) change the transcription and/or secretion of endothelium derived factors like ET-1, 2) measure the influence of such endothelial peptides and of granulocyte lipids on airway ciliary activity, characterize their receptors and delineate the signal transduction pathways that mediate their action, and 3) determine if endothelial peptides and granulocyte mediators have the ability to alter either the glycoconjugate profile of airway secretions or the epithelial glycocalyx. Such information, by improving the understanding of the ciliary and secretory defense against bacteria, may provide the basis for new treatment strategies of airway inflammation, an important feature of bronchial asthma.